EP1663126A1

EP1663126A1 - Orally effective, essentially water-free topical agent containing one or several oxidation-sensitive substances

Info

Publication number: EP1663126A1
Application number: EP04764666A
Authority: EP
Inventors: Jürgen Herbert VOLLHARDT; Cornelia RÜTTI; Philippe Emmanuel Maillan; Christine Saecker; Horst Westenfelder
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2003-09-09
Filing date: 2004-08-31
Publication date: 2006-06-07
Also published as: WO2005025527A1; BRPI0413535A; CA2535219A1; CN1849107A; CN100579504C; JP2007505064A; US20070053851A1; KR20060121866A

Abstract

The invention relates to an orally effective agent in the form of a toothpaste, a mouthwash, or a mouthwash concentrate containing one or several oxidation-sensitive substances. The invention is characterized in that said agent is provided with a water content of 7.5 percent by weight or less according to Karl Fischer.

Description

Orally active, essentially water-free topical agent containing one or more oxidation-sensitive substances

The invention relates to an orally active topical agent selected from a toothpaste, a mouthwash and a mouthwash concentrate which contains one or more substances sensitive to oxidation, in particular one or more polyphenols from green tea. Surprisingly, it has been found that the stability of such an agent can be significantly improved if the agent has a water content of not more than 7.5% by weight, based on the total weight of the agent.

A number of diseases and disorders occur in the area of the oral cavity, e.g. Dental caries, gingivitis, inflammatory processes such as, in particular, periodontitis and bad breath, which is mostly caused by volatile sulfur compounds in the oral cavity, which are caused by the constipation of sulfur-containing amino acids and proteins by oral microorganisms. Furthermore, diseases of oxidative stress can occur in the biological tissue of the oral cavity. This is also often inflammation.

For the prevention and treatment of such diseases and disorders, agents designed specifically for topical administration in the oral cavity and on the teeth, such as, in particular, dentifrices such as toothpaste or tooth gel, sprays, mouthwashes and mouthwashes are used.

A number of active ingredients for use in such agents are known. For example, WO 99/17735 discloses the use of certain chelates for the treatment of bad breath, to name just one example from the large number of publications which deal with active ingredients for oral treatment of the oral cavity. Fluorine compounds are known as active substances against tooth decay. The use of plant extracts in dental care products or products for treating the oral cavity is also widespread, and reference can be made here, for example, to WO 02/092028 or FR 2 791 893. Products with extracts from green tea are also known. Green tea has a long tradition as a remedy, particularly in East Asian folk medicine. Chen Zang, a Chinese pharmacist (Tang Dynasty, 618-907), has already handed down the saying that every medicine is only a medicine for a certain disease, but tea is a medicine for all diseases.

The main ingredients of the green tea extract are polyphenols, so-called catechins. The most widely represented catechin is (-) - epigallocatechin gallate. The green tea catechins are characterized by a very strong antioxidant effect. They also have an antimicrobial effect and are also deodorising against various bad smells. This combination of efficacies makes them principally for use in dental and oral care, e.g. interesting for the prevention or treatment of caries, gingivitis, periodontitis and bad breath. The bacterial effectiveness protects against tooth decay and gingivitis (build-up of pauque), while the antioxidant effect prevents inflammatory processes or alleviates their course. The deodorant properties reduce bad breath, on the one hand by binding bad-smelling components, but also by combating the sulfur-producing bacteria in the oral cavity due to their antimicrobial activity and thereby preventing the development of bad breath.

The use of epigallocatechin gallate, a green tea polyphenol, in oral care products is disclosed, for example, in EP 67 476.

WO 02/02096 discloses that whole body wellbeing can be improved when certain topical oral compositions are administered. Epigallocatechin gallate is mentioned as a possible active ingredient among many. The oral formulations of the publication are also not further restricted, including caramel, chewing gum, tooth powder, etc. Water is stated as a possible carrier of the oral formulations, which is generally about 5% to about 70%, preferably about 20% to about 50 % of the remedy. This value refers to all water including the water bound to auxiliary substances and to all oral formulations. The total water content is not specified for a toothpaste. About 2% to about 45% are given for the value of the water added as a carrier. The agents disclosed by way of example all contain more than 6.5% of water added as a carrier. Since the toothpastes also all contain a considerable amount of precipitated silicon dioxide, which has a considerable water content, the total water content of these agents is definitely higher than 8%. Formulations with the active ingredient epigallocatechin gallate are not produced in any of the examples. Low-water agents with the active ingredient epigallocatechin gallate are not disclosed in the publication. Storage tests were not carried out.

The use of polyphenol-containing green tea extracts in orally active topical agents is difficult because the polyphenols present in the green tea are extremely reactive. They show a very strong antioxidant effect, as a result of which degradation products form which turn formulations with such polyphenols brown after prolonged storage. Although only a small proportion of the polyphenols are usually decomposed, this is already sufficient to stain toothpastes and mouthwashes brown. A brown discoloration is unacceptable especially for dental care products and products for the treatment of the oral cavity and in particular for toothpaste formulations and mouthwashes and leads to the customer not accepting the product. These difficulties mean that to this day extracts from green tea and green tea polyphenols are not used in dental care products and products for the treatment of the oral cavity, such as toothpastes or mouthwashes.

Other active ingredients, in particular retinoids, ascorbyl compounds and ascorbic acid, resveratrol and flavonoids, also show similar difficulties in topical agents which act orally, since these compounds are also subject to oxidative degradation. Here, too, there are often colored breakdown products or a deterioration in the effectiveness of the agents.

The object of the invention is to provide new orally active topical agents which can treat the entire spectrum of diseases and disorders occurring in teeth and in the oral cavity, and which are particularly effective in caries and gingivitis, but which also reliably combat bad breath or prevent its occurrence, which are effective in the case of inflammation in the area of the oral cavity and in particular in the case of periodontosis and with which oxidative stress conditions in biological tissues of the oral cavity can also be treated. The funds are supposed to have an attractive appearance, so that they can be marketed as toothpaste and mouthwash concentrate or mouthwash and this appearance should be maintained even after prolonged storage at room temperature or at least changed less than is the case with products of the prior art.

The problem of the decomposition of substances sensitive to oxidation and in particular the discoloration of green tea polyphenols occurs with agents such as chewing gum, candy, caramel and tablets, e.g. Chewable tablets or lozenges, usually not or not as strongly, possibly because these agents are strongly colored. The problem arises in particular with toothpastes, mouthwashes and mouthwash concentrates.

The solution to this problem is based on the surprising finding that the stability of substances sensitive to oxidation and in particular of polyphenols from green tea can be considerably improved if these substances, in particular the polyphenols, are formulated in agents which have a water content of not more than 7. 5% by weight, based on the total weight of the agent. If the agents have other components that promote the decomposition of oxidation-sensitive substances, especially green tea polyphenols, in particular basic components such as e.g. Cleaning agents based on silicon dioxide or lime, which are often contained in toothpastes, can further improve the stability of the oxidation-sensitive substances, in particular the green tea polyphenols, if these constituents are conditioned with an acid.

The invention thus provides an orally active topical agent, selected from toothpastes, mouthwashes and mouthwash concentrates, containing one or more oxidation-sensitive substances and in particular green tea polyphenols, which has a water content of 7.5% by weight or less. The invention also relates to the use of oxidation-sensitive substances and in particular green tea polyphenols for the production of such an agent with a water content of 7.5% by weight or less for topical treatment of the oral cavity and / or teeth. Finally, the invention also relates to a process for reducing the decomposition of oxidation-sensitive substances and in particular the discoloration of green tea polyphenols in such an orally active topical agent, which is characterized in that the water content of the agent is 7.5% by weight or less is set. It has also been found according to the invention that water which is used in the preparation of the orally active topical compositions, that is to say added to the mixture as a carrier (“free water”), has a considerably greater effect on the stability of the substances sensitive to oxidation and in particular of the green tea polyphenols, as water, which is bound to auxiliaries and additives, such as water, which is introduced into the agent via silica gel or titanium dioxide.

The invention thus also relates to a method for producing an orally active topical agent which contains oxidation-sensitive substances and in particular green tea polyphenols, selected from toothpastes, mouthwashes and mouthwash concentrates, in which less than 2% by weight of water is used as free, non-auxiliary or additives bound water is added, and the oral agents obtainable thereby.

Unless otherwise stated or obvious, percentages always refer to the weight of an ingredient based on the total weight of the agent (% - w / w).

According to the invention, an “orally active topical agent” is understood to mean an agent which is introduced into the oral cavity and there exerts a medical, hygienic or cosmetic activity on the teeth and / or other areas of the oral cavity. According to the invention, the agents are toothpaste, mouthwashes and mouthwash concentrates. According to the invention, the term “oral cavity” is understood to mean the entire area of the mouth and throat area which is accessible for topical treatment.

A mouthwash can also be referred to as a mouthwash, but in the present case the more precise expression mouthwash is preferred since the mouthwashes according to the invention are essentially free of water. The mouthwash concentrates according to the invention are generally formulated into finished mouthwashes before use by the end user by adding a diluent, usually water.

According to the invention, the substances sensitive to oxidation are not particularly restricted. In particular, these are retinoids, ascorbyl compounds, ascorbic acid, Resveratrol, ubiquinones, flavonoids and / or green tea polyphenols. The flavonoids and particularly preferably the green tea polyphenols are preferred. Ascorbyl compounds in particular include ascorbyl phosphates, such as the ascorbyl phosphates sold under the Stay-C brand, for example sodium ascorbyl phosphate (Stay-C50).

The group of retinoids conceptually includes all retinoids that are safe for use in oral agents, including retinol and its esters, retinais and retinoic acid and its esters.

Retinol is characterized by the following structure:

Retinol (also: axerophthol; [3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2,4,6,8-nonatetraen-1-ol) is synonymous with vitamin A. ^ Analogous to the derivatives retin-1-carboxylic acid (vitamin A acid, retinoic acid, tretinoin) and their esters or retin-1 al (vitamin A aldehyde) are sometimes called vitamin A alcohol.

The retinol esters according to the invention preferably have the structure

where X preferably represents a branched or unbranched alkanoyl or alkenoyl radical of 1 to 25 carbon atoms. Retinol palmitate (= retinyl palmitate) is preferably chosen as the retinol ester. Retinal is by structure

characterized. Retinal [vitamin A1 aldehyde, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2,4,6,8-nonatetraenal] is the most stable in its all-trans form. Retinal arises from the oxidative cleavage of carotene.

Retinoic acid [vitamin A acid, all-trans-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2,4,6,8-nonatetraenoic acid] is by structure

characterized. The ester group which is optionally present instead of the hydrogen atom of the acid is preferably an alkyl group having 1 to 25 carbon atoms.

According to the invention, not only the above trans compounds, but also the corresponding compounds which have a cis configuration on one or more double bonds can be used. If the above compounds can show optical activity, both the individual enantiomers or diastereomers and any mixtures thereof, in particular racemic mixtures, can be used according to the invention. According to the invention, the ascorbic acid is in particular L-ascorbic acid {(R) -5 - [(S) -1, 2-dihydroxyethyl] -3,4-dihydroxy-5-H-furan-2-one, vitamin C} the structural formula

It is easily soluble in water, readily soluble in alcohol, insoluble in ether, petroleum ether, chloroform, benzene as well as in fats and fatty oils. Other stereochemical forms of ascorbic acid are also included.

Ascorbyl compounds are preferably understood to mean ascorbyl esters of fatty acids, particularly preferably ascorbyl palmitate. Ascorbyl compounds in the narrower sense are in particular the ascorbyl esters of the general structure

where R can represent a branched or unbranched alkyl radical having up to 25 carbon atoms.

The present invention also includes ascorbylglycosides, in particular the ascorbylglucosides, in particular the ascorbyl-2-glucoside of the structure

Ascorbyl compounds in the narrower sense are also the ascorbyl phosphates, particularly advantageously the ascorbyl 2-phosphates of ascorbic acid or its alkali metal, alkaline earth metal, zinc salts or mixed salts of such cations.

A triple deprotonated ascorbyl phosphate ion is shown above, although other deprotonation stages are also advantageous in the sense of the present invention.

The sodium, magnesium and zinc salts, for example sodium ascorbyl phosphate, are preferred.

Flavones or flavonoids are known and are often used in cosmetics or dermatology. Here, reference can be made in particular to WO 00/74641, to which reference can be made in this regard.

Flavon and its derivatives (often collectively called "flavones") are characterized by the following basic structure (substitution positions specified):

Some of the more important flavones, which can also be found in the living nature, are listed in the table below:

In nature, flavones usually occur in glycosidated form.

Other flavonoids that can be used according to the invention are flavanones

-Hydroxyflavone

aurones

and isoflavones

Oxidation-sensitive substances in the sense of the invention are also flavonoids of the generic structural formula

where Zi to Z _{7 are} independently selected from the group H, OH, alkoxy and hydroxyalkoxy, where the alkoxy or hydroxyalkoxy groups can be branched and unbranched and can have 1 to 18 carbon atoms, and wherein Gly is selected from the Group of mono- and oligoglycoside residues,

Flavonoids of the generic structural formula

where Zi to Z _{6 are} independently selected from the group H, OH, alkoxy and hydroxyalkoxy, where the alkoxy or hydroxyalkoxy groups can be branched and unbranched and can have 1 to 18 carbon atoms, and wherein Gly is selected from the Group of mono- and oligoglycoside residues, Flavonoids of the generic structural formula

where Zi to Z _{6 are} as defined above and Gly ^ Gly ₂ and Gly _{3 are} independently mono- or oligoglycoside residues,

Flavone glycosides of the structure

e.g. the structure

wherein to Z ₇ , Gly-ι, Gly ₂ and Gly _{3 are} as defined above.

Gly ₂ or Gly ₃ can also individually or together represent saturations by hydrogen atoms.

Gly, Gly _{1 f} Gly ₂ and Gly ₃ are preferably selected independently of one another from the group of the hexosyl radicals, in particular the rhamnosyl radicals and glucosyl radicals. However, other hexosyl radicals, for example allosyl, altrosyl, galactosyl, gulosyl, idosyl, mannosyl and talosyl or pentosyl radicals, can also be used.

Z ₁ to Z ₇ can preferably be selected independently of one another from the group H, OH, methoxy, ethoxy and 2-hydroxyethoxy.

Α-Glucosylrutin, α-Glucosylmyrictrin, α-Glucosylisoquercitrin and α-Glucosylquercitrin can be particularly mentioned.

Exemplary flavonoids are α-glucosylrutin, naringin (aurantiin, naringenin-7-rhamnoglucoside), hesperidin (3 ', 5,7-trihydroxy-4'-methoxyflavanon-7-rutinoside,

Hesperidoside, Hesperetin-7-O-rutinosid), Rutin (3,3 ', 4', 5,7-Pentahydroxyflyvon-3-rutinosid, Quercetin-3-rutinosid, Sophorin, Birutan, Rutabion, Taurutin, Phytomelin, Melin), Troxerutin (3,5-dihydroxy-3 ', 4', 7-tris (2-hydroxyethoxy) flavon-3- (6-O- (6-deoxy-α-L-mannopyranosyl) -ß-D-glucopyranoside) ), Monoxerutin (3,3 ', 4'5-tetrahydroxy-7- (2-hydroxyethoxy) -flavon-3- (6-O- (β-deoxy-α-L-mannopyranosyl) -ß-D-glucopyranoside)), dihydrorobinetin (3,3 ', 4', 5 '- pentahydroxyflavanone), taxifolin (3,3', 4 ', 5,7- Pentahydroxyflavanone), eriodictyol-7-glucoside (3 ', 4', 5,7-tetrahydroxyflavanone-7-glucoside), flavanone marine (3 ', 4', 7,8-

Tetrahydroxyflavanone-7-glucoside) and isoquercitrin (3,3 ', 4', 5,7-pentahydroxyflavanone-3- (β-D-glucopyranoside).

Another oxidation-sensitive substance within the meaning of the invention is resveratrol, a style derivative found in plants.

According to the invention, however, the oxidation-sensitive substances are one or more green tea polyphenols which, in particular in toothpastes, mouthwashes and mouthwash concentrates of the prior art, show strong discoloration due to oxidation and therefore make the agents commercially unattractive.

In the following, the invention is essentially explained with the aid of the particularly preferred green tea polyphenols, but the explanations also apply analogously to the other substances sensitive to oxidation, as described above.

Insofar as "green tea polyphenols" are used in the context of this invention, these are understood to mean polyphenol compounds which are present in green tea and which can be obtained from green tea in a conventional manner by extraction and, if appropriate, further separation processes, in particular by chromatographic separation processes , Of the polyphenols found in green tea, the compound (-) - epigallocatechin-3-gallate (EGCG)

the most important polyphenol compound present in the largest proportions. Other polyphenol compounds that occur in green tea are known to the person skilled in the art, and the following compounds can be mentioned here, for example:

Gallic acid GA Gallocatechin GC

Gallocatechin-3-gallate GCG (-) - epigallocatechin EGC

Catechin-3-gallate CG (-) - Epicatechin-3-gallate ECG (-) - Epicatechin EC

If the green tea polyphenols are optically active substances, a reference to such a substance means a reference to each individual stereoisomer, in particular each of the optically active enantiomers (preferably to the naturally occurring optically active enantiomer) and to any mixtures thereof, especially on racemates.

According to the invention, the term “green tea polyphenols” encompasses all polyphenols present in green tea, but in particular the compounds mentioned above, and very particularly the compound (-) - epigallocatechin-3-gallate. The green tea polyphenols can be obtained in the usual way from green tea, for example by extracting the leaves of the green tea with hot water, which gives an extract which is obtained from approx. 40% polyphenols and its typical ingredients in Table 1

Ingredient polyphenol fraction (% of dry matter)

Flavanols (contains eg EGCG) 25.0 flavonols and flavonol glycosides 3.0 phenolic acids and epsides 5.0 other polyphenols 3.0 caffeine 3.0 theobrom in 0.2 Remaining ingredients

Amino acids 4.0

Organic acids 0.5

Monosaccharides 4.0

Polysaccharides 13.0

Cellulose 7.0

Protein 15.0

Lignin 6.0

Lipids 3.0

Chlorophyll and other pigments 0.5

Ash 5.0

Volatile ingredients 0.1

which are based on the publication by Ballentine D.A. et al., 1997, The NetherlandsCrit Rev Food Sei Nutr. 1997 Dec; 37 (8): 693-704, to which full reference is made in this regard.

The green tea polyphenols or flavones in the extract e.g. as follows: mg / 100 mg of dried tea leaves (%)

EGCG (epigallocatechin gallate) 13.37 73.99

EGC (epigallocatechin) 0.44 2.43

ECG (epicatechin gallate) 2.91 16.10

EC (epicatechin) 0.55 3.04

C (catechin) 0.02 0.1 1

GCG (Gallocatechin Gallate) 0.26 1.44

GA (gallic acid) 0.52 2.89

According to the invention, an aqueous extract of green tea, as described above, can be used, if appropriate after further concentration, to reduce the water content in the preparation of the agents according to the invention. However, the remaining ingredients are preferably separated off as far as possible, so that only the green tea polyphenols are used. The extract used preferably contains at least 30%, if appropriate after chromatic purification, more preferably at least 50%, more preferably at least 70%, in particular at least 80%, for example at least 90%, most preferably at least 95% of green tea polyphenols, in particular the green tea polyphenols specified above, in each case stated as% of the dry matter. A chromatographically purified product is particularly preferably used, and even more preferably a purified product in which the content of epigallocatechin gallate is increased as much as possible, for example to 80% or more, preferably to 90% or more, based on the total amount of green tea -Polyphenols, each stated in% of the dry weight. According to the invention, epigallocatechin gallate is particularly preferably used as green tea polyphenol, which is purified as far as possible and contains only minor traces (5% or less, preferably 3% or less, more preferably 2% or less) of the other green tea polyphenols, each indicated in % of dry matter.

The aqueous green tea extract can be purified chromatographically in a manner known per se, such as, for example, in Separation of individual catechins from green tea using silica gel column chromatography and HPLC. Journal of Food Lipids (2003), 10 (2), 165-177. CODEN: JFFLES ISSN: 1065-7258. Reference can also be made to EP-A 1 077 211, EP-A 1 103 550, US-A 6,210,679, WO-A 97/30597 and WO-A 95/18540, which disclose corresponding work-ups of the green tea extract and to which reference is made. Although it is also possible to use the aqueous green tea extract without chromatographic purification, the aqueous extract of the green tea polyphenols often already contains brown-colored degradation products of the green tea polyphenols, which gives the agent according to the invention a slightly brown discoloration. In individual cases, this may still be acceptable, provided that this discoloration is not too strong, since the discoloration does not increase significantly when the agent according to the invention is stored, when using purified green tea extract and in particular when using a chromatographically separated polyphenol fraction as described above, this problem can be avoided, however, and the topical agents obtained orally show a particularly attractive color.

The content of green tea polyphenols in the agent according to the invention is not particularly restricted. The content of oxidation-sensitive substances, in particular green tea polyphenols, is usually 0.01% by weight to 10% by weight, preferably 0.05 to 8% by weight, for example 0.1 to 5% by weight. amount, each based on the total weight of the agent according to the invention. Also preferred is a content of oxidation-sensitive substances, in particular green tea polyphenols, but also in ascorbic acid and derivatives thereof, retinoids, in particular retinol, but also retinyl derivatives such as retinyl palmitate, resveratrol and ubiquinone, from 0.01 to 5% by weight, in particular from 0 , 01 to 3 wt .-%, for example from 0.01 to 2 wt .-%.

Toothpaste, mouthwashes and mouthwash concentrates containing epigallocatechin-3-gallate in an amount of 0.01 to 10% by weight, more preferably 0.05 to 8% by weight and in particular 0.1 to 5 are particularly preferred according to the invention % By weight, based in each case on the total weight of the composition.

While usually a considerable proportion of water is used in orally active topical compositions, since water is an excellent physiologically compatible carrier material, it is essential according to the invention that the compositions contain no more than 7.5% by weight of water, based on the total weight of the By means of otherwise oxidative decomposition of the oxidation-sensitive substances or discoloration of the green tea polyphenols occurs when the agents are stored, which gives the agents an unacceptable brown discoloration, especially if the agents are toothpaste, mouthwash or mouthwash concentrates. The water content in toothpaste and mouthwashes or mouthwash concentrates is usually much higher, for example DE-A 42 37 500 describes toothpastes with a water content of well over 30% by weight and WO 02/02096 also goes from 5% to 70% % Water content in oral formulations and adds more than 6.5% free water to the preparation of the agents disclosed by way of example, so that the water bound to auxiliaries and additives results in a total water content of in any case more than 8%.

In the agents according to the invention, the water content is preferably not more than 6.5% by weight, more preferably not more than 4.8% by weight and most preferably not more than 1.9% by weight, in each case based on the Total weight of the product. Insofar as a water content is specified in the context of this application, the information relates to the water content as determined by the known Karl Fischer method, unless stated otherwise or is obvious to a person skilled in the art. Karl Fischer's water determination is described, for example, in "Karl Fischer Titration: Determination of Water (Chemical Laboratory Practice / Instructions for Chemical Laboratory Practice, Vol. 20, Eugene Scholz, Springer Verlag, 1984"). According to the invention, it was surprisingly found that, in particular, the water (free water) used as carrier during the preparation of the composition according to the invention adversely affects the stability of the oxidation-sensitive substances and in particular the green tea polyphenols, while water bound to auxiliaries and additives has less adverse effect on the stability. When mixing the agents according to the invention, therefore, preferably less than 2% by weight of free water is used, more preferably 1.5% by weight or less, more preferably 1.0% by weight or less, more preferably 0.5% by weight. % or less, most preferably no free water is used at all. According to the invention, “free water” is understood to mean water which is present as a liquid and is not adsorptively or bound as crystalline water to solid substances such as silica gel, sorbitol or titanium dioxide. The amount of free water in the agent according to the invention results from the amount of water used as a carrier in the preparation.

According to the invention, it has also surprisingly been found that in many cases the stability of oxidation-sensitive substances, in particular green tea polyphenols, in topical agents which act orally can be increased further if constituents of these agents which can impair the stability of the oxidation-sensitive substances, in particular green tea polyphenols , acidifying conditioning, ie treatment with an acidic agent. If, despite the low water content in the agents according to the invention, there is still a decomposition of the oxidation-sensitive substances, in particular discoloration due to decomposition of the green tea polyphenols, it can be determined by means of a few routine tests which additives of the agent favor the decomposition and these additives can then undergo acidifying conditioning are subjected, whereby the compatibility of the additives is improved and the stability of the agent according to the invention, in particular the discoloration due to degradation products of the green tea polyphenols, is further restricted. Such additives, which are particularly incompatible with green tea polyphenols but also with other oxidation-sensitive substances, are compounds which react in a basic manner, i.e. Compounds that produce a pH of more than 7 in aqueous suspension or solution.

Such basic additives are often used in particular in toothpastes, and in particular the cleaning bodies based on silicon dioxide which are frequently present in toothpastes can be used to decompose the substances sensitive to oxidation, in particular the Green tea polyphenols, contribute to brown-colored and brown-colored decomposition products.

The decomposition of the oxidation-sensitive substances, in particular the discoloration of the green tea polyphenols, is therefore reduced even more according to the invention if additives which are incompatible with the oxidation-sensitive substances, in particular the green tea polyphenols, e.g. a basic cleaning body, in particular a cleaning body based on silicon dioxide, e.g. Silicic acid gel or based on lime, as is often used in toothpastes, are subjected to an acidifying conditioning step, that is to say a treatment with an acid-reacting compound (addition of the acid-reacting compound to the incompatible additive). The toothpastes according to the invention preferably contain a basic cleaning body, in particular a cleaning body based on silicon dioxide or aluminum dioxide, such as silica gel or aluminum hydroxide, preferably in an amount from 10% by weight to 30% by weight, more preferably from 10% by weight to 20% by weight.

In the context of this invention, “acid-reacting compounds” are all compounds which, in a 1% solution or dispersion, have a pH of less than 7.0, more preferably a pH of 6.0 or less, even more preferably a pH - Deliver a value of 5.0 or below, especially 4.0 or below. Suitable acidifying conditioning can be carried out, for example, with citric acid, e.g. with 50% citric acid. The conditioning can either be done in a separate step, the basic compound, e.g. the cleaning body based on silicon dioxide is treated in a first step with the acid-reacting compound and then added to the agent according to the invention, or it can be carried out in the formulation of the agent according to the invention, as is preferred and is explained in more detail in the examples. The agents according to the invention therefore preferably contain an acid-reacting compound e.g. Citric acid.

The acid-reacting compound is preferably present in an amount of 0.05 to 5%, in particular 0.1 to 3%, in the agent according to the invention, in particular in the toothpaste according to the invention.

The oral topical agents according to the invention are, for example, toothpastes which represent the center and the basis of every dental care and are therefore frequent contain oxidation-sensitive substances or form the most suitable platform for the application of the multi-active effects of green tea phenols. Another important product form in dental care is mouthwash. In addition to an antimicrobial effect, they are particularly valued for their deodorization. Green tea polyphenols also offer a double effect here. The oral topical agents according to the invention are therefore toothpastes, mouthwashes or mouthwash concentrates.

The orally active topical agents according to the invention can be pharmaceuticals, cosmetic products or hygiene products. Common ingredients and additives of the toothpastes, mouthwashes and mouthwash concentrates according to the invention are known to the person skilled in the art and are described in relevant standard works such as formulation technology, H. Mollet, A. Grubenmann, Wiley VCH 2000. The agents according to the invention can in particular also contain further active substances, such as antibacterial active substances, for example further extracts of natural products, which have an antibacterial effect. Further possible additives of the agents according to the invention are, for example, conventional anti-caries agents such as phosphates, pyrophosphates, polyphosphates, phosphonates, polyphosphonates and mixtures thereof. Also polyacrylates or polycarboxylates, polyepoxysuccinates, ethylenediaminetetraacetic acid, nitrilotriacetic acid and similar compounds, agents for the prevention of tartar and plaque, agents which can release fluoride ions such as sodium fluoride, potassium fluoride, tin fluoride, ammonium fluoride and mixtures thereof, desensitizing agents, potassium nitrate extracting agents and pain relievers, and anti-painkillers of natural products and non-steroidal anti-inflammatory agents, agents for combating bad breath as conventional antimicrobial agents such as triclosan, phthalic acid and Phthalsäuresalze, chlorhexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride, N-tetradecylpyridinium chloride, tetradecyl-4-ethylpyridinium chloride, Octenifin , Delmopinol, octapenol and other piperidine derivatives, nicin preparations, agents that release zinc or tin ions, antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline and metronidazole and methyl salicylates as well as metal cations and mixtures thereof usually used for this purpose can be used to prepare the agents according to the invention. A good overview of conventional additives in orally active topical agents can be found, for example, in WO 02/092028, to which reference is made in full in this regard. The toothpastes according to the invention can furthermore be customary polishing materials (or a cleaning body) such as silicon dioxide, aluminum dioxide, phosphates and mixtures thereof, such as, for example, dicalcium orthophosphate dihydrate, calcium pyrophosphate,

Contain tricalcium phosphate, aluminum hydroxide, silica gel, etc. Lime can also be included as a cleaning body; in practice, ground or precipitated lime is used in particular. Polyethylene fine powder can also be used as a cleaning body, e.g. Fine powder with <10 μm particle size, e.g. is distributed by the company BASF, Ludwigshafen, Germany. The toothpastes can also contain other conventional additives, e.g. Anionic, amphoteric, zwitterionic, cationic or nonionic surfactants or mixtures thereof, antioxidants, agents for changing the tooth color such as in particular agents for whitening the teeth, minerals, vitamins and nutrients, sweeteners, humectants, fillers, thickeners, alkali metal bicarbonates, buffers, colorants, flavorings , etc. In this regard, reference is again made to WO 92/092028.

The agents according to the invention will also contain at least one carrier material. A preferred carrier for the toothpastes which is particularly preferred according to the invention is glycerol, but other non-aqueous carriers known in the art, such as propylene glycol and polyglycerol, can also be used. The mouthwash concentrates or mouthwashes can be produced on the basis of alcohol (ethanol) or alcohol-free. Non-alcoholic mouthwash concentrates have the advantage that they can also be used safely by children. Alcohol-containing mouthwash concentrates can be produced, for example, on the basis of a glycerol-ethanol mixture. A suitable carrier material for alcohol-free mouthwash concentrates is e.g. Glycerin, propylene glycol and polyglycerin.

The products according to the invention are produced in a manner known per se, analogously to processes known in the prior art, such as those e.g. are described in WO 02/092028, to which reference is made in this regard.

The following examples illustrate the invention. example 1

From the following ingredients (in% w / w)

A) Glycerin (anhydrous) ad 100 epigallocatechin gallate (EGCG) 0.10 Texapon N70 (sodium lauryl sulfate) 1, 42 sodium fluoride 0.22 sodium saccharin 0.10 Carbopoi 981 (carbomer) 0.70 Syloblanc δl (silica gel) 10.00 Syloblanc 82 ( Silica gel) 10.00

B) Citric acid 0.45 water (aqua) 0.30 100.00

Toothpaste was prepared by first mixing all the substances listed under A) individually in the order given at room temperature with slow stirring. Stirring was continued until a homogeneous paste was formed. In a separate vessel, the substances specified under B) were mixed at room temperature with slow stirring and added to the homogeneous paste at room temperature. It was mixed again until a homogeneous paste was formed. The homogeneous paste is suitable as toothpaste and contains 0.1% by weight epigallocatechin gallate. The total water content according to Karl Fischer was 4.7%.

Comparative Example 1

For comparison, a toothpaste with 0.1% by weight epigallocatechin gallate of the following composition (data in% w / w)

Water ad 100 glycerin 20.00 epigallocatechin gallate (EGCG) 0.10 Texapon N70 (sodium lauryl sulfate) 1, 42 sodium fluoride 0.22 sodium saccharin 0.10 Carbopol 981 (carbomer) 1, 40 Syloblanc δl (silica gel) 10.00 Syloblanc 82 (silica gel ) 10.00 100.00

prepared in which all listed substances were mixed together in the order given at room temperature with slow stirring. Stirring was continued until a homogeneous paste was formed. The total water content according to Karl Fischer was 59%.

Test example 1

The two toothpastes from Example 1 and Comparative Example 1 were stored for eight weeks at room temperature (25.degree. C.) and independently of this for eight weeks at 5.degree. C., and then the color was assessed colorimetrically. The colorimetric assessment was based on a CIE 1976 L xaxb "Colorspace" assessment as described in "Color Physics for Industry" by Roderick McDonald, Society of Dyers & Colorists, March 1997. The value ΔE results from ΔE = [(L - L ₀ ) ² + (a - a ₀ ) ² + (b - b ₀ ) ² ] ^1/2 from a so-called color space, where L stands for brightness, positive values a red colors mean negative values for a green colors mean positive values for b yellow colors and negative values for b blue colors. The color measurements were carried out with a Minolta Spectrophotometer CM-3600d. The result of the comparison is shown in FIG. 1. It can be seen that even at 5 ° C. the toothpaste according to the invention shows significantly less discoloration than the comparative product on an aqueous basis. The difference becomes particularly clear at room temperature. Even at room temperature, the toothpaste according to the invention is more stable than the comparison product when stored at only 5 ° C. The toothpaste of the comparative example on an aqueous basis was so discolored after eight weeks of storage at room temperature that the toothpaste is no longer suitable for commercial purposes. In contrast, the toothpaste according to the invention showed only a slight discoloration, which does not interfere with commercial use.

In FIG. 1, VB means the toothpaste of the comparative example and EM means the toothpaste according to the invention. ΔE indicates the "colorspace" rating.

Example 2

A mouthwash concentrate with the ingredients (in% w / w)

A) Glycerin ad 100 sodium saccharin 1, 80

B) Epigallocatechin gallate (EGCG) 2.50 alcohol (ethanol) 62.50 propylene glycol 5.00 100.00

was prepared by mixing sodium saccharin with glycerin at room temperature with slow agitation. In a separate vessel, epigallocatechin gallate was dissolved in ethanol at room temperature. The propylene glycol was added with stirring at room temperature. The mixture of components B) was added to the mixture of components A). An alcohol / glycerin-based mouthwash concentrate with 2.5% epigallocatechin gallate was obtained. The total water content according to Karl Fischer was less than 0.5%. Comparative example 2

A comparative mouthwash concentrate which, as is customary in the prior art, contains water and the ingredients (data in% w / w)

A) Water ad 100 glycerin 5.00 sodium saccharin 1.80

B) Epigallocatechin gallate (EGCG) 2.50 alcohol (ethanol) 62.50 100.00

was prepared by dissolving sodium saccharin in water at room temperature and then adding glycerin. In a separate vessel, epigallocatechin gallate was dissolved in ethanol at room temperature and components B) were mixed with components A). The total water content according to Karl Fischer was 29%.

Test example 2

The mouthwash concentrates from Example 2 and Comparative Example 2 were stored for three months at room temperature and independently of this for three months at 5 ° C. A colorimetric determination was then carried out as in test example 1 and the result is shown in FIG. While the discoloration of the mouthwash concentrate is still acceptable at 5 ° C for the comparative product, the discoloration of the comparative product at room temperature after three months of storage is so high that the product is no longer commercially usable. There is also a certain discoloration in the mouthwash according to the invention, but this is considerably less than the discoloration of the comparative product.

In FIG. 2, VB means the mouthwash concentrate from the comparative example and EM means the mouthwash concentrate according to the invention from example 2. ΔE indicates the "colorspace" rating. Example 3

A mouthwash concentrate with the ingredients (in% w / w)

A) Glycerin ad 100 sodium saccharin 1, 80

B) Epigallocatechin gallate (EGCG) 2.50

C) Perfume oil (Peppermint 450-150 Düllberg) 2.50 propylene glycol 30.00 100.00

was prepared by mixing sodium saccharin with glycerin at room temperature with slow agitation. Epigallocatechin gallate was then added and stirring was continued until the epigallocatechin gallate was completely dissolved. In a separate vessel, components C) were mixed at room temperature and then added to the mixture of A) and B). An alcohol-free mouthwash concentrate containing 2.5% epigallocatechin gallate was obtained. The total water content according to Karl Fischer was less than 0.5%.

Examples 4 to 17

Toothpastes were prepared in a conventional manner from the constituents given in the following tables. The toothpastes were stored at different temperatures and after two weeks and after three weeks the content of the reaction-sensitive substance was determined in the usual way. The results are also shown in the following tables. In all toothpastes, the total water content according to Karl Fischer was less than 0.5%. 4. Toothpaste with ascorbic acid

5. Toothpaste with sodium ascorbyl phosphate (Stay-C50)

Toothpaste with retinol

Toothpaste with retinyl paimitat

5. Toothpaste with resveratrol

9. Toothpaste to prevent deposits

10. Toothpaste with Flavon

11. Toothpaste with flavonol

12. Toothpaste with chrisin

13. Toothpaste with galangin

14. Toothpaste with apigenin

15. Toothpaste with fisetin

16. Toothpaste with quercetin

17. Toothpaste with ubiquinone

Claims

Expectations:

1. Oral topical agent in the form of a toothpaste, a mouthwash or a mouthwash concentrate containing one or more oxidation-sensitive substances, characterized in that the agent has a Karl Fischer water content of 7.5% by weight or less.

2. Oral topical agent according to claim 1, characterized in that the oxidation-sensitive substances are selected from retinoids, ascorbyl compounds, ascorbic acid, resveratrol, flavonoids and / or green tea polyphenols.

3. Orally active topical agent according to claim 2, characterized in that it contains one or more green tea polyphenols.

4. Oral topical agent according to claim 3, characterized in that it contains one or more green tea polyphenols in an amount of 0.01 to 10 wt .-%, based on the weight of the agent.

5. Orally active topical agent according to claim 3 or 4, characterized in that it contains epigallocatechin gallate.

6. Oral topical agent according to one of claims 3 to 5, characterized in that it contains an extract from green tea.

7. Oral topical agent according to one of claims 1 to 6, characterized in that it has a water content according to Karl Fischer of 4.8 wt .-% or less.

8. Oral topical composition according to claim 7, characterized in that it has a water content according to Karl Fischer of 3 wt .-% or less.

9. Oral topical agent according to one of claims 1 to 8, characterized in that the agent is a toothpaste.

10. Orally active topical composition according to claim 9, characterized in that the toothpaste contains a cleaning body with a basic reaction, preferably a cleaning body based on silicon dioxide or lime.

11. Oral topical agent according to claim 9, characterized in that the toothpaste contains polyethylene fine powder as a cleaning body.

12. Oral topical agent according to one of claims 1 to 8, characterized in that the agent is a mouthwash or a mouthwash concentrate.

13. Orally active topical agent according to one of claims 1 to 12, characterized in that it further contains an acid-reacting compound.

14. Oral topical agent according to claim 13, characterized in that the acidic compound is citric acid.

15. Oral topical agent according to one of claims 1 to 14, characterized in that less than 2% by weight of free water has been added to it.

16. Use of an oxidation-sensitive substance for the production of a toothpaste, a mouthwash or a mouthwash concentrate with a Karl Fischer water content of 7.5% by weight or less for topical treatment of the oral cavity and / or teeth.

17. Use according to claim 16, characterized in that the agent for the prevention and / or treatment of caries, gingivitis and / or bad breath.

18. Use according to claim 16, characterized in that the agent for the prevention and / or treatment of inflammatory processes in the oral cavity.

19. Use according to claim 18, characterized in that the inflammatory processes in the oral cavity are periodontitis.

20. Use according to claim 16, characterized in that the agent is an agent for the prevention and / or for the treatment of oxidative stress conditions in the biological tissue of the oral cavity.

21. Use according to one of claims 16 to 20, wherein the oxidation-sensitive substance is selected from retinoids, ascorbyl compounds, ascorbic acid, resveratrol, flavonoids and / or green tea polyphenols.

22. Use according to claim 21, wherein the oxidation-sensitive substance is one or more green tea polyphenols.

23. A method for stabilizing an oxidation-sensitive substance in an orally active topical agent selected from toothpaste, mouthwash or mouthwash concentrate, characterized in that the water content of the agent according to Karl Fischer is set to 7.5% by weight or less.

24. The method according to claim 23, characterized in that the oxidation-sensitive substance is formulated with an acid-reacting compound.

25. The method according to claim 23 or 24, characterized in that the oxidation-sensitive substance is selected from retinoids, ascorbyl compounds, ascorbic acid, resveratrol, flavonoids and / or green tea polyphenols.

26. The method according to claim 25, characterized in that the oxidation-sensitive substance is one or more green tea polyphenols and the discoloration of the green tea polyphenols in the orally active topical agent is reduced by the method.

27. A process for producing an orally active topical agent selected from toothpaste, mouthwash and mouthwash concentrate, in which an oxidation-sensitive substance is mixed with conventional carriers and additives, characterized in that less than 2% by weight of water is used as the carrier.

28. The method according to claim 27, characterized in that 1, 5% water or less is used as carrier.

29. The method according to claim 27 or 28, characterized in that the oxidation-sensitive substance is selected from retinoids, ascorbyl compounds, ascorbic acid, resveratrol, flavonoids and / or green tea polyphenols.

30. The method according to claim 29, characterized in that the oxidation-sensitive substance is one or more green tea polyphenols.

31. Oral topical agent selected from toothpaste, mouthwash and mouthwash concentrate, obtainable by a process according to any one of claims 27 to 30.